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Novel vaccine antigens against N. gonorrhoeae

针对淋病奈瑟菌的新型疫苗抗原

基本信息

批准号：
10700802
负责人：
Paola Massari
金额：
$ 55.13万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-08 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10700802
关键词：
Adjuvant Adjuvant Study Amino Acid Sequence Antibiotic Resistance Antibiotics Antibodies Antibody Formation Antibody Specificity Antigens Avidity Bacteria Bacterial Adhesion Binding Bioinformatics CD4 Positive T Lymphocytes Ceftriaxone Cells China Clinical Combined Vaccines Complement Detection Disease Dose Drug-resistant Neisseria Gonorrhoeae Epithelial Cells Epitopes FDA approved Female Gene Proteins Genes Goals Gonorrhea Growth Human Hydrogen Peroxide Hypothetical Protein IL17 gene IL8 gene Immune Immune response Immunity Immunize Immunoglobulin A Immunoglobulin G In Vitro Inbred BALB C Mice Individual Infection Infertility Inflammatory Interferon Type II Interleukin-1 beta Interleukin-4 Interleukin-6 Invaded Irrigation Knowledge Lead Lipid A Measures Mediating Membrane Messenger RNA Metals Monoclonal Antibodies Morbidity - disease rate Mucous Membrane Multi-Drug Resistance Mus Neisseria gonorrhoeae Nutrient Depletion Oxygen Phylogenetic Analysis Probability Production Property Proteins Reporting Research Design Sampling Serum Sexually Transmitted Agents Sexually Transmitted Diseases Site Specimen Splenocyte Structure Subgroup Surface T-Cell Proliferation T-Lymphocyte TNF gene Therapeutic Time Urethra Vaccine Antigen Vaccines Vagina Vaginal Douching Vesicle Virulence Woman Work aluminum sulfate antimicrobial peptide bacterial fitness bactericide cervicovaginal cohort cross reactivity cytokine design efficacy evaluation fitness immunogenicity improved in vivo lipooligosaccharide mRNA Expression male mouse model mutant novel novel vaccines peptidomimetics pharmacologic pre-clinical reproductive tract response tool transcriptome transcriptome sequencing vaccine candidate vaccine evaluation vaccine formulation

项目摘要

Neisseria gonorrhoeae is the causative agent of the sexually transmitted infection (STI) gonorrhea, a disease with high morbidity worldwide, estimated at 87 million cases annually, and severe reproductive tract complications in women. Current treatment approaches against gonorrhea are compromised by recent onset of antibiotic resistance. There is a pressing need for an effective vaccine against N. gonorrhoeae, but protective antigens have been limited, so far. Our previous work on the gonococcal transcriptome during human natural infection has described differences in mRNA expression of gonococcal genes in urethral and vaginal lavage samples fromnaturally-infected subjects as compared to mRNA expression when the correspondinggonococcal strains were cultured in vitro. We termed those genes “in vivo-expressed factors” (IVEFs). We also reported that ~30% of the gonococcal genes expressed during infection are hypothetical proteins. We hypothesized that gonococcal hypothetical proteins expressed and regulated during infection include new candidate antigens for a vaccine against N. gonorrhoeae. Through a bioinformatics-based candidate antigen selection strategy (CASS) that examined predicted immunogenicity, cellular localization, conservation in N. gonorrhoeae and structure features of the gonococcal hypothetical proteins, we identified 36 new potential targets (ongoing R21AI131004). We investigated an initial group of 6 antigens, confirming 3 as surface-exposed proteins (NGO0690, NGO0948 and NGO1701) that induced cross-reactive antibodies with complement-mediated serum bactericidal activity (SBA) against diverse N. gonorrhoeae strains. In preliminary studies, a combination of these antigens showed promise as protective vaccine candidates in a mouse model of gonococcal infection. Correlates of protection against gonorrhea in humans are not known but SBA and reduced vaginal colonization in mice are stepping- stones in preclinical gonococcal vaccine evaluation. An example is the (currently most advanced) N. gonorrhoeae vaccine candidate, the 2C7 LOS epitope (and its mimotope TCMP2). Other cited mechanisms of protection include antibody-dependent inhibition of bacterial adhesion or invasion of host cells at the colonization site, but these have yet to be confirmed in human studies. The goal of this project is to validate and improve the efficacy of our three candidates as gonococcal vaccine antigens. In Aim 1, we propose antigen dosing and adjuvant studies to achieve optimal immune responses to our candidates and SBA; in Aim 2 we will validate protection in the available female mouse model of gonococcal vaginal colonization, broaden strain coverage by including TMCP2, and correlate immune effector mechanisms and protection; in Aim 3, we will define the function of the hypothetical protein candidates and their impact on N. gonorrhoeae virulence, fitness and Immunity, a necessary complement for their selection as vaccine candidates. Our studies will provide new tools and knowledge towards the unmet goal of a successful vaccine against N. gonorrhoeae.

淋病奈瑟菌是性传播感染（STI）淋病的病原体，全世界发病率高，估计每年有8700万例，女性的并发症。目前针对淋病的治疗方法受到最近发生的淋病的影响。抗生素耐药性目前迫切需要一种有效的抗N.淋病，但保护性到目前为止，抗原是有限的。我们以前对人类自然过程中淋球菌转录组的研究感染描述了尿道和阴道灌洗液中淋球菌基因mRNA表达的差异当相应的淋球菌感染时，菌株在体外培养。我们将这些基因称为“体内表达因子”（IVEFs）。我们还报道说，在感染期间表达的淋球菌基因中，约30%是假设蛋白质。我们假设在感染过程中表达和调节的淋球菌假设蛋白包括新的候选抗原，抗N.淋病通过基于生物信息学的候选抗原选择策略（卡斯）检测了N.淋病与结构淋球菌假设蛋白的特征，我们确定了36个新的潜在靶点（正在进行的R21 AI 131004）。我们研究了最初的一组6种抗原，确认3种为表面暴露蛋白（NGO 0690，NGO 0948 和NGO 1701），其诱导具有补体介导的血清杀菌活性的交叉反应性抗体 (SBA)反对不同的N.淋病菌株。在初步研究中，这些抗原的组合显示，有望作为淋球菌感染小鼠模型的保护性候选疫苗。保护的相关因素对人类淋病的作用尚不清楚，但SBA和小鼠阴道定植的减少正在逐步- 临床前淋球菌疫苗评价中的结石。一个例子是（目前最先进的）N。淋病疫苗候选者，2C 7 LOS表位（及其模拟表位TCMP 2）。其他引述的机制保护包括抗体依赖性抑制细菌粘附或在定植时侵入宿主细胞但这些尚未在人体研究中得到证实。本项目的目标是验证和改进我们的三种候选抗原作为淋球菌疫苗抗原的有效性。在目标1中，我们提出抗原剂量和佐剂研究，以实现对我们的候选人和SBA的最佳免疫应答;在目标2中，我们将验证在可用的淋球菌阴道定植雌性小鼠模型中提供保护，通过包括TMCP 2，以及相关的免疫效应机制和保护;在目标3中，我们将定义功能的假设蛋白质候选人和他们的影响N。淋病毒力、适应性和免疫力是选择它们作为候选疫苗的必要补充。我们的研究将提供新的工具和知识，以实现一个成功的疫苗对N。淋病